ABSTRACT The overall goal of this proposed project is to better understand the impact of the gut microbiome on rectal transmission of Human Immunodeficiency Virus Type-1 (HIV) and the incomplete immune reconstitution and increased immune activation and inflammation after viral suppression by combined anti-retroviral therapy (ART). We hypothesize that the gut microbiome plays an important role in determining the susceptibility to rectal transmission of HIV and in restoring normal immune cell populations in the gut after suppressive ART treatment. Therefore, the proposed studies are designed to fill critical knowledge gaps about how the gut microbiome impacts HIV infection and gut immune function. In order to close these knowledge gaps, we will use our double humanized mouse model that has been developed in our lab to answer two important questions. First, does the composition of the gut microbiome impact host susceptibility to rectal HIV infection? This information could be critical for developing novel prevention strategies and for informing vaccine design. Secondly, how does the gut microbiome impact gut immune cell reconstitution as well as elevated systemic inflammation and immune activation during suppressive ART treatment? This information could be used to develop new therapeutic strategies to restore gut immune cell populations to pre-infection levels, resolve persistent inflammation and immune activation, and decrease morbidity in HIV infected patients.